Method and device for handling specimens

ABSTRACT

An apparatus for use with an array of liquid specimen containers having open upper ends includes a panel structure having an array of openings corresponding to the array of liquid specimen containers such that the open upper ends of the containers will be aligned with the openings upon placement of the panel structure over the containers in an upright engagement with the containers. The apparatus further includes filter material stretched across the openings so as to extend across the open upper ends of the containers in overlying abutment with the open upper ends of the containers when the panel structure is in the upright engagement. In this arrangement, liquid contents of the containers can flow downward through the filter material when the panel structure and the containers are together moved from their upright engagement to an overturned engagement inverted from their upright engagement.

[0001] This application is a division of copending U.S. patentapplication Ser. No. 09/180,356, filed Apr. 12, 1999.

FIELD OF THE INVENTION

[0002] The present invention is generally in the field of laboratoryhandling of liquid specimens and more specifically concerns amulti-compartment plate capable of containing a plurality of liquidspecimens and a method and system utilizing same.

BACKGROUND OF THE INVENTION

[0003] Processing of liquid specimens to test a variety of parameterstherein, is a standard endeavor in research as well as in day-to-dayclinical diagnostics. In order to reduce costs and increase efficiencyof such method, improved accuracy and eliminate sources for error, thereis a growing tendency to develop and use automated systems in which aplurality of liquid specimens are simultaneously handled. One devicecommon in most such methods is a plate comprising a plurality of liquidholding compartments in which the liquid specimens may be incubated.

[0004] A variety of methods involve filtering of the specimen through afilter medium, a medium following incubation, in order to view theretentate remaining on the filter. Prior art devices allowingsimultaneous incubation and subsequent simultaneous filtration of aplurality of liquid specimens are multi-compartment plates where thebottom wall of the compartments is constituted by a filter. Such is thecase, for example, in the device disclosed in U.S. Pat. Nos. 4,493,815;5,047,215 and 5,223,133. The filter for which such an application has asmall pore size, does not readily enable seepage of liquid therethroughand only upon the application of a vacuum, the liquid is forced to flowthrough the filter. However, there is always some absorbance of liquidspecimen onto the filter sheet, which may be significant in case ofsmall specimens. In addition, in long incubation processes, inparticular in such involving agitation of the specimens, there may alsobe some leakage of liquid through the filters even without theapplication of the vacuum.

[0005] In devices where the filter is permanently attached to the bottomwall of the compartment, there is an inherent difficulty in viewing theretentate, as this has to be through the opening of the compartment, bythe use of long field optics.

[0006] When using a filter medium removable from the bottom wall, thereis a very serious problem of ensuring a firm, leakage-proof attachmentof the filter to the bottom of the compartments, which is a difficultfeat to achieve simultaneously for all the compartments in a plate.

SUMMARY OF THE INVENTION

[0007] The present invention has, as one its objects, the provision of anovel device for simultaneous handling of a plurality of liquidspecimens. It is particularly the object of the invention to providesuch a device useful in procedures requiring filtration of the liquidspecimens following incubation or any other treatment of the specimenwithin the compartment.

[0008] It is another object of the invention to provide a novel methodfor the simultaneous treatment of a plurality of liquid specimens andthen filtering the specimens through a filter sheet for subsequentviewing of the retentate on the filter.

[0009] It is a further object of the invention to provide a novel systemfor simultaneous treatment of a plurality of liquid specimens andsubsequent filtration of the specimens through a filter sheet.

[0010] Other objects of the invention will be clarified from reading ofthe following text.

[0011] The present invention provides, by a first of its aspects, adevice in the form of a plate comprising a plurality of compartments,each compartment being adapted to hold a liquid specimen and having anaperture at its top for introducing and withdrawing liquid into and fromthe compartment, respectively; each compartment has a vent opening at aside wall at about mid portion thereof between the compartment's top andbottom.

[0012] The present invention provides a filter device for filteringspecimens contained in a multi-compartmental plate comprising a planarbody with a top and bottom face, having a plurality of openings, and afilter sheet stretched to cover all openings, the device beingattachable to said plate at its top face with each opening being inregister with and attached to an aperture of one compartment, such thatthe filter is stretched over said aperture to allow vacuum filtration ofspecimens from the compartments through the filter.

[0013] In accordance with a preferred embodiment, the filter sheet isstretched over said bottom face. In accordance with another preferredembodiment, said filter device cooperates with a support member attachedto the bottom face of the filter device for supporting the filter duringthe vacuum filtration. Typically, the filter sheet is stretched bycooperation stretching members in such filter device and in said supportmember, e.g. projections in one and recesses in the other for receivingthe projections.

[0014] In accordance with another aspect of the invention there isprovided a method for processing a plurality of liquid specimens,comprising:

[0015] a) providing a multi-compartmental plate which comprises aplurality of compartments each adapted to hold a liquid specimen andhaving an aperture at its top for introducing or removing of liquid anda vent opening within the compartment at a mid-portion thereof;

[0016] b) introducing each one of the plurality of liquid specimens intoone of the plate's compartments;

[0017] c) treating or incubating the specimens contained in thecompartments;

[0018] d) attaching a filter sheet to the plate such that it covers theopenings of the compartments and propelling the liquid through thefilter sheet; and

[0019] e) separating the filter sheet from the plate and viewingparticulate retentate remaining on the filter sheet.

[0020] A further aspect of the present invention is concerned with asystem for simultaneous processing of a plurality of liquid specimens,comprising:

[0021] i. a multi-compartmental plate as defined above;

[0022] ii: a filtration assembly comprising a filter device as definedabove, and preferably also said support device.

[0023] A unique feature of the multi-compartmental plate, the method orsystem of the invention is in that the filter sheet is attached to theplate only at the end of the specimen's treatment process, just prior tofiltration. Thus, in accordance with the invention there is no contactbetween the filter sheet and the liquid specimen until that stage.

[0024] A particular preferred application of the invention is in thefield of assaying liquid specimens, both in research and in clinicaldiagnostics, in order to qualify or quantify the presence, type ofcharacteristics of living matter contained therein, e.g. to diagnosemicroorganismal infection in a body fluid.

[0025] The invention will now be illustrated, by way of example only, bysome non-limiting specific embodiments, with reference to the annexeddrawings.

BRIEF DESCRIPTION OF THE DRAWINGS

[0026]FIG. 1 is an isometric view of a multi-compartmental plate inaccordance with an embodiment of the invention;

[0027]FIG. 2 is a partial isometric cross-sectional view of a singlecompartment taken along line II-II in FIG. 1;

[0028]FIG. 3A is a cross-sectional view, taken along lines III-III inFIG. 1, showing the two members which are joined together to form themulti-compartmental plate;

[0029]FIG. 3B is an exploded view of FIG. 3A showing the twoconstituents of the plate;

[0030]FIG. 4 is an isometric view of a filtering assembly, in accordancewith an embodiment of the invention, for use in conjunction with themulti-compartmental plate of FIG. 1;

[0031]FIG. 5 is an exploded isometric view showing the threeconstituents of the filtering assembly;

[0032]FIG. 6 is a cross-section through line VI-VI in FIG. 4;

[0033]FIG. 7 is an isometric view of the multi-compartmental plate andthe filtration assembly during their attachment to one another forfiltration of the liquid specimen contained in the compartments of themulti-compartmental plate;

[0034]FIG. 8 is an isometric view showing all the components together ona vacuum stage during filtration;

[0035]FIG. 9 is a cross-section through line IX-IX in FIG. 8 during thefiltration process (without the vacuum stage) in an upright position(with the filtration assembly on top of the plate);

[0036]FIG. 10 shows the sequence of operation of using amulti-compartmental plate of the invention, represented here by a singlecompartment.

[0037]FIG. 10A shows the compartment prior to inoculation of a specimen;

[0038]FIG. 10B shows an empty compartment during specimen and reagentinoculation.

[0039]FIG. 10C shows the compartment after attachment of the filtrationassembly;

[0040]FIG. 10D shows the compartment after inversion and prior toapplication of a vacuum;

[0041]FIG. 10E shows the compartment during the vacuum applicationstage;

[0042]FIG. 10F shows an empty compartment after complete withdrawal ofthe liquid with a retentate remaining on the filter sheet;

[0043]FIG. 10G shows the step of inspection of the retentate of thefilter sheet; and

[0044]FIG. 11 is an isometric view of a filtration assembly inaccordance with another embodiment of the invention, comprisingindependent filter device and support body;

[0045]FIG. 12 is a partial cross-sectional view along the lines XII-XIIin FIG. 11; and

[0046]FIG. 13 is a partial, exploded cross-sectional view along thelines XII-XII in FIG. 11.

DESCRIPTION OF THE EMBODIMENTS

[0047] Reference is first being made to FIGS. 1-3 showing amulti-compartmental plate in accordance with the invention. The plategenerally designated 20 has a plurality of compartments 22, adapted tohold liquid, each having upper diverging portion 24 ending in anaperture 26 having an annular rim 27. Each of compartments 22 has anassociated L-shaped venting duct 28 having an opening 29 at amid-portion 30 of the compartment and another opening 31 at the end ofan upright direct portion 32 projecting upwards from the top face 33 ofthe plate. As can be seen particularly in FIG. 2, the bottom portion 36of the compartment has an inverted dome-shape.

[0048] The plate has a circumferencial frame 34 with a dove-tailingengaging member 35 adapted to be engaged by an appropriate member of amanipulation (not shown).

[0049] As can be seen particularly in FIG. 3, plate 20 is assembled froman upper member 42 and a lower member 44 which are typically combined byultrasonic welding. As can further be seen, the upper member has aplurality of bosses 46 which are adapted to accommodate duct-definingprojection 48 both of which form together projection 32.

[0050]FIGS. 4, 5 and 6, show the filtering assembly 50 having an upperface 52 comprising a plurality of openings 54 each of whichcorresponding to and adapted to receive on aperture 26 of compartment22. With particular reference to FIG. 5, it can be seen that filteringassembly 50 is assembled from a base, bottom member 56, a filter sheet58 and a filter retaining and stretching, upper member 60. Base member56 comprises a plurality of annular projections 62 with openings 64.Openings 64 are the upper ends of converging ducts 66 ending towards abottom face 67 of member 56 with a bottom opening 68. As can further beseen in FIG. 6, member 60 has a plurality of downward projections 70interposed between openings 54.

[0051] Once the three components of assembly 50 are assembled together,filter sheet 58 is tensioned over opening 64 by the combined action ofannular projection 62 and downward projection 70, ensuring a tight,leakage proof fit between filter sheet 58 and opening 64.

[0052] With reference now to FIG. 7, it can be seen that for filtrationof liquid specimens contained in the compartments 22 of plate 20, thefiltration assembly 50 is turned upside down and its upper face 52 isattached to the upper face 33 of plate 20. Each of openings 54 of plate50 correspond to and are in register with aperture 26 in plate 20. Onceengaged, the entire assembly 80 consisting of plate 20 and filterassembly 50 is inverted and can be placed on a vacuum stage 82, as canbe seen in FIG. 8. Vacuum stage 82 is connected to a vacuum system 84consisting of a vacuum unit 86 and a liquid disposing reservoir 88. Withreference to FIG. 9, it can be seen that at this state the annular rim27 is snugly held within opening 54 and aperture 26 tightly engagesfilter sheet 58 and consequently, once the vacuum is applied, a liquidspecimen contained in compartment 22 is drawn through the filter sheet58 and through duct 66, via outlet 68 to the liquid reservoir 88.

[0053] A sequence of operation in a system of the invention can be seenin FIGS. 10A-10G. At an initial stage (FIG. 10A) the multi-compartmentalplate is held with the aperture 26 of each of the compartments facingupwards, allowing inoculation of liquid specimens 100 and optionally areagent solution 102, by means of a suitable pipettor 104 (FIG. 10B).Following incubation, the multi-compartmental plate 20 is engaged withthe filtering assembly 50 (FIG. 10C), as explained above, (FIG. 10C) andthis entire assembly 80 is then inverted (FIG. 10D). Then followingapplication of a vacuum, liquid is drawn through the filter (FIG. 10E),as already explained above, and after emptying of the compartment, theparticulate matter 106 contained in the specimen is retained on sheet 58(FIG. 10F). Finally, plate 20 can be removed and discarded and thefiltration assembly can then be taken as is for viewing of the retentate106 by a microscope 108, optionally forming part of a computerized imageonly in system (not shown).

[0054] Reference is now being made to FIGS. 11-13 relating to anembodiment of a filtering assembly 120, which unlike filtering assembly60, comprises two individual, separable components, namely filter device122 and filter support member 124. Filter device 122 is generally aplanar member with a top face 126 and a bottom face 128 with a pluralityof openings 130. Filter device 122 has a peripheral skirt 132 upwardprojecting reinforcing ribs 134 and downward tensioning projections 136.Filter 138 is stretched between edges of the device 122 and attached tothe edges of the device 122 by ultrasonic welding, gluing, etc. Device122 further comprises a dovetail engagement portion 140, to allowmanipulation of the device by a robotic arm.

[0055] Filter support member 124 has a frame 142 with a shoulder 144adapted to receive and fit with skirt 132 of filter device 122. Device124 has a plurality of openings 146, each one formed between a pair ofribs 148, each of which has an indention 150 for receiving downwardprojections 136 of device 122. Filter support member in the embodimentshown has also a dovetail engagement portion 152.

[0056] Filter 128 is initially retained and stretched between the edgesof device 122, as can be seen in FIG. 13. Once the two devices, namelyfilter device 122, as can be seen in FIG. 13. Once the two devices,namely filter device 122 and filter support member 124 are attached toone another, as shown in FIG. 12, the filter becomes stretched over ribs148. Typically, device 122 will first be attached to multi-compartmentalplate at its top face 126, and then the two together will be attached tofilter support member 124, so as to form the filtration assembly.Alternatively, the two components of the filtration assembly, namelydevices 122, 124 may first be attached to one another and then both ofthem together will be attached to a multi-coompartmental plate. Forviewing of the particulate retentate remaining on the filter, filterdevice 122 is detached from filter supported member 124 and brought to amicroscope similarly as the filter assembly as shown in FIG. 10G.

[0057] A particular preferred implementation of a multi-compartmentalplate and the above described system is in processing of biologicalliquid specimens, e.g. urine specimens. In accordance with thispreferred embodiment, the liquid specimen is incubated for a time toallow cells to multiply and increase their number, for a time sufficientto allow absorption of a dye into the cells, etc. Then after filtration,as described above, the cellular material retained on filter sheets canbe viewed, characterized or counted. The viewing of the retained matteris preferably by means of an automated image analysis system.

[0058] Viewing of the retentate can, for example, be by means ofepifluorescence. However, it is possible also, to use bottomelimination.

[0059] In addition to processing and using particulate matter, the plateand system of the invention may be used also for a variety of otherapplications, e.g. analysis of crystals formed following a chemicalreaction in the liquid specimen.

[0060] Preferably, all the components of the system are disposable,although they can also be made to be suitable for reuse, aftersterilization.

[0061] While the entire system may be used manually, a particularlypreferred implementation of the system is for automatic, robotutilizing, processing system.

1. An apparatus for use with an array of liquid specimen containershaving open upper ends, said apparatus comprising; a panel structurehaving an array of openings corresponding to the array of liquidspecimen containers such that the open upper ends of the containers willbe aligned with said openings upon placement of said panel structureover the containers in an upright engagement with the containers; andfilter material stretched across said openings so as to extend acrossthe open upper ends of the containers in overlying abutment with theopen upper ends of the containers when said panel structure is in saidupright engagement, whereby liquid contents of the containers can flowdownward through said filter material when said panel structure and thecontainers are together moved from said upright engagement to anoverturned engagement inverted from said upright engagement.
 2. Anapparatus as defined in claim 1 wherein said filter material is a singlefilter sheet.
 3. An apparatus as defined in claim 1 wherein said filtermaterial is fixed to said panel structure.
 4. An apparatus as defined inclaim 1 wherein said panel structure is configured for the open upperends of the containers to extend into said openings when said panelstructure is in said upright engagement with the containers.
 5. Anapparatus as defined in claim 1 wherein said panel structure includes afirst panel having said openings, and further includes a second panelhaving openings aligned with said openings in said first panel; and saidfilter material is located between said first and second panels.
 6. Anapparatus as defined in claim 5 wherein said second panel further has aplurality of duct structures projecting from said openings in saidsecond panel in directions away from said openings in said first panel.7. An apparatus as defined in claim 5 wherein said first panel hasprojections engaging and stretching said filter material toward saidsecond panel.
 8. An apparatus as defined in claim 7 wherein said secondpanel has indentations in which said projections are received.
 9. Anapparatus as defined in claim 7 wherein said second panel hasprojections engaging and stretching said filter material toward saidfirst panel.
 10. An apparatus as defined in claim 1 wherein said panelstructure includes a first panel having said openings, and furtherincludes a second panel having openings aligned with said openings insaid first panel; said filter material is located between said first andsecond panels; and said second panel has projections engaging andstretching said filter material toward said first panel.
 11. Anapparatus as defined in claim 10 wherein said projections on said secondpanel have annular configurations surrounding said openings in saidsecond panel.
 12. An apparatus as defined in claim 10 wherein said firstpanel is configured for the open upper ends of the containers to extendinto said openings in said first panel when said panel structure is insaid upright engagement; and said projections on said second panel haveterminal end surfaces located radially inward of said openings in saidfirst panel, whereby said terminal end surfaces limit movement of theupper ends of the containers into said openings in said first panel uponmovement of said panel structure into said upright engagement with thecontainers.